This project will exmine the role of the kidney in glucose metabolism in nondiabetic and diabetic dogs. It will establish the contribution of renal glucose production (RGP) and renal glucose utilization (RGU) to systemic glucose kinetics under physiologic conditions and in diabetes, and to investigate the hormonal and substrate regulation of renal glucose turnover in vivo. Our preliminary data indicate that RGP equals RGU and accounts for about 30% of endogenous glucose appearance in the postabsorptive dog. We hypothesize that glucose handling by the kidney is critical to fuel homeostasis and that the renal response to insulin deficiency plays an important role in the hyperglycemia of diabetes. First, we plan to test whether autoregulation by glucose is operative in the kidney as it is in the liver, and whether hyperglycemia which saturates tubular reabsorption of glucose coincides both with maximal stimulation of RGU and suppression of RGP, rendering the effect of hyperinsulinemia on these processes redundant. Since gluconeogenesis is increased in diabetes, we will determine whether increased free fatty acid and amino acid availability, typically seen with insulin deficiency, stimulate RGP and gluconeogenesis, and whether these are suppressed by hyperinsulinemia. Hypoglycemia occurs frequently in patients with chronic renal failure, particularly in diabetes. We will test the hypotheses that RGP increases and RGU decreases in the recovery from hypoglycemia induced by insulin. Finally, we will study the effects of short-term insulin deficiency on renal glucose metabolism and its response to peripheral and intraportal insulin replacement. All studies will be performed in conscious dogs; 10-14 days prior to the experiment, catheters will be implanted in the left renal vein, left renal artery and the femoral artery under general anesthesia; doppler flow probes will be placed around the left and right renal arteries for subsequent continuous measurement of renal blood flow. Selected dogs will undergo total pancreatectomy and catheters will be placed in the portal vein. Primed constant peripheral infusions of [3-3H]glucose, [2-14C]glycerol and insulin, together with intrarenal infusion will be utilized. This research will provide considerable additional information regarding the contribution of RGP and RGU to systemic glucose metabolism in the postabsorptive state and in uncontrolled diabetes mellitus. In addition, the proposed studies will characterize in detail the regulation of RGP and RGU by free fatty acids, amino acids, insulin and glucose itself. We anticipate that these studies will lead to analogous studies in nondiabetic and diabetic humans.